Fused bicyclic pyrimidine derivatives

ABSTRACT

A novel fused bicyclic pyrimidine derivative or a salt thereof that acts as a tachykinin receptor antagonist and, in particular, as an NK1 receptor antagonist is represented by the following general formula (1):  
                 
 
wherein the rings A and B are each a benzene ring having 1 to 3 substituents (any adjacent two of which may be bound to one another to form a ring); the ring C is a nitrogen-containing ring; R is a hydrogen atom, a C 1  to C 6  alkyl group, a C 1  to C 6  alkylcarbonyl group, or a C 1  to C 6  alkylsulfonyl group; m is 1 or 2; and n is 2 or 3.

TECHNICAL FIELD

The present invention relates to novel fused bicyclic pyrimidinederivatives and pharmaceutically acceptable salts thereof that act astachykinin receptor antagonists. The present invention also relates tomedical applications of such compounds.

TECHNICAL BACKGROUND

‘Tachykinin’ is a collective term for such neuropeptides as substance P,neurokinin A, and neurokinin B. These tachykinins are known to exhibitvarious physiological activities by binding to corresponding receptorsin a human body (neurokinin 1 (NK1), neurokinin 2 (NK2), and neurokinin3 (NK3), respectively). Of different tachykinins, substance P, asidefrom its role as a neurotransmitter in primary sensory neurons incentral and peripheral nervous systems, brings about variousphysiological effects, such as diuresis, excitation of neurons,increased blood vessel permeability, blood vessel dilation, contractionof smooth muscles, and immune activities. Substance P is also believedto play significant roles in the onset of various pathologicalconditions such as pollakiuria, incontinence, vomiting, inflammation,allergies, respiratory tract disorders, pains, and central nervoussystem disorders. Thus, a need exists for the development of a compoundthat acts as a tachykinin receptor antagonist and, in particular, as anNK1 receptor antagonist and is thus suitable for use as an effectiveprophylactic or therapeutic agent against various pathologicalconditions such as those mentioned above. It is also desirable that sucha compound offer high safety, persistence of efficacy, and otheradvantageous characteristics.

At present, the following compounds are known as NK1 receptorantagonists and are described in the following publications:

(1) European Patent Application Publication No. EP-A-429366 describescompounds such as the one represented by the following formula:

(2) PCT pamphlet (International Patent Publication) No. WO91/09844describes compounds such as the one represented by the followingformula:

(3) European Patent Application Publication No. EP-A-532456 describescompounds such as the one represented by the following formula:

(4) European Patent Application Publication No. EP-A-522808 describescompounds such as the one represented by the following formula:

(5) PCT pamphlet (International Patent Publication) No. WO93/01169describes compounds such as the one represented by the followingformula:

(6) Japanese Patent Laid-Open Publication No. Hei 8-67678 describes acompound represented by the following formula and salts thereof:

wherein the rings A and B are each a homocyclic or heterocyclic ringwith at least one of the rings A and B being a heterocyclic ring; thering C is a benzene ring; R is H or a hydrocarbon residue; one of X andY is —NR¹— (where R¹ is H or a hydrocarbon residue) or —O— and the otheris —CO— or —CS—, or one of X and Y is —N═ and the other is ═CR— (whereR² is H, a halogen, a hydrocarbon residue, an amino, or a hydroxylgroup); and n is 1 or 2.

(7) Japanese Patent Laid-Open Publication No. Hei 9-104674 describes acompound represented by the following formula:

wherein Y is a nitrogen or oxygen atom which may or may not be alkylatedor acylated; R¹ is a hydrogen atom, a lower alkyl group, a loweralkanoyl group, an alkyl group having a nitrogen atom, a carbamoylgroup, a lower alkylthio group, a lower alkylsulfinyl group, a loweralkylsulfonyl group, or a (4-phenylpiperadine-1-yl)methyl group; R² is ahydrogen atom, a lower alkyl group, a lower alkyl group having ahydroxyl group, a lower alkanoyl group, or a lower alkoxy group; and therings A and B are each a substituted or unsubstituted benzene ring.

(8) Japanese Patent Laid-Open Publication No. Hei 9-263585 describes acompound represented by the following formula:

wherein the ring M is a heterocyclic ring in which the structural moiety—X═Y<is —N═C<, —CO—N<, or —CS—N<; R^(a) and R^(b) may together form thering A, or R^(a) and R^(b) are each independently a hydrogen atom or asubstituent of the ring M; the rings A and B are each independently asubstituted or unsubstituted homocyclic or heterocyclic ring, providedthat at least one of the rings A and B is a substituted or unsubstitutedheterocyclic ring; the ring C is a substituted or unsubstitutedhomocyclic or heterocyclic ring; the ring Z is a substituted orunsubstituted ring; and n is an integer from 1 to 6.

(9) Japanese Patent Laid-Open Publication No. Hei 11-246559 describes acompound represented by the following formula:

wherein X is a nitrogen atom or a CH group; R¹ is a hydrogen atom, alower alkyl group, an aryl group, or an aralkyl group; R² is a hydrogenatom or a lower alkyl group; the rings A and B are each independently asubstituted or unsubstituted benzene ring; and n is 1 or 2.

(10) Japanese Patent Laid-Open Publication No. 2000-139834 describes acompound represented by the following formula:

wherein R¹ and R² are each independently a hydrogen atom or an C₁ to C₆alkyl group; R³ is a hydrogen atom, a substituted or unsubstituted C₁ toC₆ alkylcarbonyl group, a substituted or unsubstituted C₁ to C₆alkylsulfonyl group, a substituted or unsubstituted C₁ to C₆ alkylgroup, a substituted or unsubstituted arylmethyl group or analkoxycarbonyl group; the ring A is a homocyclic or heterocyclic ringwhich may include 1 through 3 independently selected substituents (anyadjacent two of which may be bound to one another to form a ring); thering B is a benzene ring which may include 1 through 5 substituents (anyadjacent two of which may be bound to one another to form a ring); andthe ring C is a benzene ring which may include 1 through 3 substituents(any adjacent two of which may be bound to one another to form a ring).

(11) Japanese Patent Laid-Open Publication No. 2000-247957 describes acompound represented by the following formula:

wherein R is a hydrogen atom or the like; R¹ is a hydrogen atom or thelike; R² and R^(2,) are each a hydrogen atom or the like; R³ is ahydrogen atom or the like; R⁴ is a hydrogen atom or the like; R⁵ is ahydrogen atom or the like; R⁶ is a hydrogen atom or the like; X is—C(O)N(R⁵)— or the like; n is an integer from 0 to 4; and m is 1 or 2.

(12) PCT pamphlet (International Patent Publication) No. WO00/50401describes a compound represented by the following formula:

wherein R is a hydrogen atom or the like; R¹ is a hydrogen atom or thelike; R² is a hydrogen atom or the like; R³ is a hydrogen atom or thelike; R⁴ is a hydrogen atom or the like; R⁵ is a hydrogen atom or thelike; R⁶ is a hydrogen atom or the like; X is —C(O)N(R⁵)— or the like; nis an integer from 0 to 4; and m is 1 or 2.

(13) PCT pamphlet (International Patent Publication) No. WO00/73279describes a compound represented by the following formula:

wherein R¹ is a hydrogen atom or the like; R² is a hydrogen atom or thelike; R³ is a hydrogen atom or the like; R⁴ and R⁴, are each a hydrogenatom or the like; R⁵ is a lower alkyl group or the like; n is an integerfrom 0 to 2; and X is—C(O)N(R⁴″)—or the like.

(14) PCT pamphlet (International Patent Publication) No. WO00/73278describes a compound represented by the following formula:

wherein R¹ is a hydrogen atom or the like; R² is a hydrogen atom or thelike; R³ is a hydrogen atom or the like; R⁴ and R⁴, are each a hydrogenatom or the like; R⁵ is a lower alkyl group or the like; R⁶ is ahydrogen atom or the like; n is an integer from 0 to 2; and X is—C(O)N(R⁴″)—or the like.

DISCLOSURE OF THE INVENTION

At present, no effective tachykinin antagonists (in particular, NK1receptor antagonists) are known that can serve as prophylactic ortherapeutic agents against the above-described pathological conditionsand at the same time meet requirements for pharmaceutical products,including safety, persistence of efficacy, pharmacokinetics, andpharmacological activities.

It is thus an objective of the present invention to provide a novelcompound that acts as an effective tachykinin receptor antagonist and,in particular, as an NK1 receptor antagonist and can thus serve as aprophylactic or a therapeutic agent against various tachykininreceptor-related pathological conditions, including increased urinaryfrequency, incontinence of urine, vomiting, inflammation, allergies,respiratory tract disorders, pains, and central nervous systemdisorders.

The present inventors have discovered that fused bicyclic pyrimidinederivatives as represented by the following general formula (1), orsalts thereof, can act as effective tachykinin receptor antagonists (inparticular, as NK1 receptor antagonists):

wherein the rings A and B are each a benzene ring that may include 1through 3 substituents (any adjacent two of which may be bound to oneanther to form a ring); the ring C is a nitrogen-containing ring; R is ahydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆ alkylcarbonyl group,or a C₁ to C₆ alkylsulfonyl group; m is 1 or 2; and n is 2 or 3. Asevidence, the present inventors have demonstrated in animal experimentsthat these compounds can effectively relieve dysuria, atachykinin-mediated disorder. This discovery led the present inventorsto ultimately complete the present invention.

Accordingly, the present invention provides the followings:

(I) A fused bicyclic pyrimidine derivative represented by the followinggeneral formula (1), or a salt thereof:

-   -   wherein the rings A and B are each a benzene ring, which may        have 1 to 3 substituents (any adjacent two of which may be bound        to one another to form a ring) that are each independently        selected from the group consisting of a halogen atom, a C₁ to C₆        alkyl group, which may be substituted with a halogen atom, and a        C₁ to C₆ alkoxyl group;    -   the ring C is a 5- to 7-membered nitrogen-containing ring, which        may contain, aside from the nitrogen atom, 1 to 3 heteroatoms        selected from the group consisting of a nitrogen atom, a sulfur        atom, and an oxygen atom;    -   the ring C may further contain a substituent (a substituent        selected from the group consisting of a C₁ to C₆ alkyl group, a        hydroxyl group, a C₁ to C₆ alkoxyl group, a formyl group, a C₁        to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group, a        carbamoyl group, a mono- or di-substituted C₁ to C₆        alkylcarbamoyl group, a C₁ to C₆ alkylsulfonyl group, an amino        group, a mono- or di-substituted C₁ to C₆ alkylamino group, a C₁        to C₆ alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino        group, a C₁ to C₆ alkylsulfonylamino group, an oxo group, a        6-membered aromatic heterocyclic group, and a substituent        represented by the following formula:    -   wherein the ring D is a 3- to 7-membered nonaromatic        heterocyclic ring, which may contain, aside from the nitrogen        atom, 1 to 3 heteroatoms selected from the group consisting of a        nitrogen atom, a sulfur atom, and an oxygen atom and may further        contain 1 or 2 oxo-substituted carbon atoms);    -   R is a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆        alkylcarbonyl group, or a C₁ to C₆ alkylsulfonyl group;    -   m is 1 or 2; and    -   n is 2 or 3.

(II) The fused bicyclic pyrimidine derivative according to (I) aboverepresented by the following general formula (1a), or a salt thereof:

-   -   wherein the ring A is a benzene ring, which may have 1 to 3        substituents (any adjacent two of which may be bound to one        another to form a ring) that are each independently selected        from the group consisting of a halogen atom, a C₁ to C₆ alkyl        group, which may be substituted with a halogen atom, and a C₁ to        C₆ alkoxyl group;    -   the ring C is a 5- to 7-membered nitrogen-containing ring, which        may contain, aside from the nitrogen atom, 1 to 3 heteroatoms        selected from the group consisting of a nitrogen atom, a sulfur        atom, and an oxygen atom;    -   the ring C may further contain a substituent (a substituent        selected from the group consisting of a C₁ to C₆ alkyl group, a        hydroxyl group, a C₁ to C₆ alkoxyl group, a formyl group, a C₁        to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group, a        carbamoyl group, a mono- or di-substituted C₁ to C₆        alkylcarbamoyl group, a C₁ to C₆ alkylsulfonyl group, an amino        group, a mono- or di-substituted C₁ to C₆ alkylamino group, a C₁        to C₆ alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino        group, a C₁ to C₆ alkylsulfonylamino group, an oxo group, a        6-membered aromatic heterocyclic group, and a substituent        represented by the following formula:    -   wherein the ring D is a 3- to 7-membered nonaromatic        heterocyclic ring, which may contain, aside from the nitrogen        atom, 1 to 3 heteroatoms selected from the group consisting of a        nitrogen atom, a sulfur atom, and an oxygen atom and may further        contain 1 or 2 oxo-substituted carbon atoms);    -   R is a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆        alkylcarbonyl group, or a C₁ to C₆ alkylsulfonyl group; and    -   n is 2 or 3.

(III) The fused bicyclic pyrimidine derivative according to (II) above,or a salt thereof, wherein in the general formula (1a), the ring C isrepresented by the following formula:

-   -   wherein R¹ is a hydroxyl group, a C₁ to C₆ alkoxy group, a        formyl group, a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆        alkoxycarbonyl group, a carbamoyl group, a mono- or        di-substituted C₁ to C₆ alkylcarbamoyl group, an amino group, a        mono- or di-substituted C₁ to C₆ alkylamino group, a C₁ to C₆        alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino group,        a C₁ to C₆ alkylsulfonylamino group, an oxo group, a 6-membered        aromatic heterocyclic group, or a substituent represented by the        following formula:    -   wherein the ring D is a 3- to 7-membered nonaromatic        heterocyclic ring, which may contain, aside from the nitrogen        atom, 1 to 3 heteroatoms selected from the group consisting of a        nitrogen atom, a sulfur atom, and an oxygen atom and may further        contain 1 or 2 oxo-substituted carbon atoms.

(IV) The fused bicyclic pyrimidine derivative according to (II) above,or a salt thereof, wherein in the general formula (1a), the ring C isrepresented by the following formula:

-   -   wherein X is —O— or —S(O)_(q)—; and q is 0, 1, or 2.

(V) The fused bicyclic pyrimidine derivative according to (II) above, ora salt thereof, wherein in the general formula (1a), the ring C is agroup represented by the following formula:

-   -   wherein R² is a hydrogen atom, a C₁ to C₆ alkyl group, a formyl        group, a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl        group, a carbamoyl group, a mono- or di-substituted C₁ to C₆        alkylcarbamoyl group or a C₁ to C₆ alkylsulfonyl group; and r is        1 or 2.

(VI) The fused bicyclic pyrimidine derivative according to (II) above,or a salt thereof, wherein in the general formula (1a), the ring C isrepresented by the following formula:

-   -   wherein R²′ is an acetyl group or a methylsulfonyl group; and r        is 1 or 2.

(VII) The fused bicyclic pyrimidine derivative according to (II) above,or a salt thereof, wherein in the general formula (1a) above, the ring Cis represented by the following formula:

(VIII) The fused bicyclic pyrimidine derivative according to (VII)above, or a salt thereof, wherein in the general formula (1a) above, nis 3.

(IX) The fused bicyclic pyrimidine derivative according to (VII) above,or a salt thereof, wherein in the general formula (1a), R is a hydrogenatom, and n is 3.

(X) A tachykinin receptor antagonist containing as an active ingredientthe fused bicyclic pyrimidine derivative according to any one of (I)through (IX) above, or a salt thereof.

(XI) An NK1 receptor antagonist containing as an active ingredient thefused bicyclic pyrimidine derivative according to any one of (I) through(IX) above, or a salt thereof.

(XII) A prophylactic or therapeutic agent for dysuria, includingdefective bladder functions such as increased urinary frequency andincontinence of urine, containing as an active ingredient the fusedbicyclic pyrimidine derivative according to any of (I) through (IX)above, or a salt thereof.

(XIII) A prophylactic or therapeutic agent for disorders of digestivetract such as ulcerative colitis and Crohn's disease, containing as anactive ingredient the fused bicyclic pyrimidine derivative according toany of (I) through (IX) above, or a salt thereof.

(XIV) A prophylactic or therapeutic agent for vomiting induced byexposure to X-ray, chemotherapy, pregnancy, migraine, postoperativepains, decreased gastrointestinal motility, and side effects of drugs,containing as an active ingredient the fused bicyclic pyrimidinederivative according to any of (I) through (IX) above, or a saltthereof.

(XV) A therapeutic agent for treating conditions, such as asthma,coughing, ache, migraine, tooth pain, and rheumatoid arthritis,containing as an active ingredient the fused bicyclic pyrimidinederivative according to any of (I) through (IX) above, or a saltthereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will now be described in detail.

Rings A and B

In the general formula (1), the rings A and B each independentlyrepresent a benzene ring, which may include 1 to 3 substituents (anyadjacent two of which substituents may be bound to one another to form aring). The substituents on each of the rings A and B may be positionedat any possible position with the number of the substituents on eachring varying from about 1 to 3. Any adjacent two of these substituentsmay be bound to each other to form a ring. Examples of the substituentson the rings A and B include halogen atoms, C₁ to C₆ alkyl groups, whichmay be substituted with halogen atoms, and C₁ to C₆ alkoxyl groups.

Examples of the halogen atoms include fluorine atom, chlorine atom,bromine atom, and iodine atom.

Examples of the “C₁ to C₆ alkyl groups that may be substituted withhalogen atoms” include methyl group, ethyl group, propyl group,isopropyl group, isobutyl group, sec-butyl group, tert-butyl group,fluoromethyl group, chloromethyl group, bromomethyl group, iodomethylgroup, 1-fluoroethyl group, 1-chloroethyl group, 2-chloroethyl group,difluoromethyl group, trifluoromethyl group, trichloromethyl group, and2,2,2-trifluoroethyl group.

Examples of the “C₁ to C₆ alkoxyl groups” include methoxy group, ethoxygroup, propoxy group, isopropoxy group, isobutoxy group, sec-butoxygroup, and tert-butoxy group.

Examples of the “rings in which two adjacent substituents are bound toeach other to form a ring” include the followings:

Ring A

Preferred examples of the ring A are those represented by the followingformulae:

wherein R³, R⁴, and R⁵ are each independently a fluorine atom, achlorine atom, a methyl group, an ethyl group, a trifluoromethyl group,or a methoxy group.

Particularly preferred examples of the ring A are those represented bythe following formulae:

Ring B

Preferred examples of the ring B are those represented by the followingformulae:

wherein R⁶, R⁷, and R⁸ are each independently a fluorine atom, achlorine atom, a methyl group, an ethyl group, a trifluoromethyl group,or a methoxy group.

Particularly preferred examples of the ring B are those represented bythe following formulae:

Ring C

The ring C is a 5- to 7-membered nitrogen-containing ring that may besubstituted and may contain, aside from the nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom. Examples of “5- to 7-memberednitrogen-containing rings that may contain, aside from a nitrogen atom,1 to 3 heteroatoms selected from the group consisting of a nitrogenatom, a sulfur atom, and an oxygen atom” include 5-membered aromaticheterocyclic rings that may contain, aside from a nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom (such as pyrrole, imidazole, pyrazole,triazole, and tetrazole rings) and 5- to 7-membered nonaromaticheterocyclic rings that may contain, aside from a nitrogen atom, 1 to 3heteroatoms selected from the group consisting of a nitrogen atom, asulfur atom, and an oxygen atom (such as tetrahydropyridine,dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine,tetrahydropyridazine, dihydropyrrole, dihydroimidazole, dihydropyrazole,dihydrooxazole, dihydroisooxazole, piperidine, piperazine,hexahydropyrimidine, hexahydropyridazine, morpholine, thiomorpholine,homopiperidine, homopiperazine, pyrrolidine, imidazolidine,pyrazolidine, tetrahydrooxazole, tetrahydroisooxazole rings.).

Examples of “optional substituents on the ring C” include a C₁ to C₆alkyl group, a hydroxyl group, a C₁ to C₆ alkoxy group, a formyl group,a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group, acarbamoyl group, a mono- or di-substituted C₁ to C₆ alkylcarbamoylgroup, a C₁ to C₆ alkylsulfonyl group, an amino group, a mono- ordi-substituted C₁ to C₆ alkylamino group, a C₁ to C₆ alkylcarbonylaminogroup, a C₁ to C₆ alkoxycarbonylamino group, a C₁ to C₆alkylsulfonylamino group, an oxo group, a 6-membered aromaticheterocyclic group, and a group represented by the following formula:

(wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ringthat may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms).

Examples of the “C₁ to C₆ alkyl group” include methyl group, ethylgroup, propyl group, isopropyl group, isobutyl group, sec-butyl group,and tert-butyl group.

Examples of the “C₁ to C₆ alkoxy group” include methoxy group, ethoxygroup, propoxy group, isopropoxy group, isobutoxy group, sec-butoxygroup, and tert-butoxy group.

Examples of the “C₁ to C₆ alkylcarbonyl group” include acetyl group,propionyl group, and butyryl group.

Examples of the “C₁ to C₆ alkoxycarbonyl group” include methoxycarbonylgroup, ethoxycarbonyl group, isopropoxycarbonyl group, andt-butoxycarbonyl group.

Examples of the “mono- or di-substituted C₁ to C₆ alkylcarbamoyl group”include methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoylgroup, isopropylcarbamoyl group, t-butylcarbamoyl group, hexylcarbamoylgroup, dimethylcarbamoyl group, diethylcarbamoyl group,dipropylcarbamoyl group, diisopropylcarbamoyl group, dibutylcarbamoylgroup, and dihexylcarbamoyl group.

Examples of the “C₁ to C₆ alkylsulfonyl group” include methylsulfonylgroup, ethylsulfonyl group, and propylsulfonyl group.

Examples of the “mono- or di-substituted C₁ to C₆ alkylamino group”include methylamino group, ethylamino group, propylamino group,isopropylamino group, t-butylamino group, hexylamino group,dimethylamino group, diethylamino group, dipropylamino group,diisopropylamino group, dibutylamino group, and dihexylamino group.

Examples of the “C₁ to C₆ alkylcarbonylamino group” include acetylaminogroup, propionylamino group, and butyrylamino group.

Examples of the “C₁ to C₆ alkoxycarbonylamino group” includemethoxycarbonylamino group, ethoxycarbonylamino group,t-butoxycarbonylamino group, and hexyloxycarbonylamino group.

Examples of the “C₁ to C₆ alkylsulfonylamino group” includemethylsulfonylamino group, and ethylsulfonylamino group.

Examples of the “6-membered aromatic heterocyclic group” include pyridylgroup, pyrazyl group, pyrimidyl group, and pyridazinyl group.

Examples of the “functional group represented by the following formula:

(wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ringthat may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms)” include azetidino group, pyrrolidino group, piperidino group,morpholino group, thiomorpholino group, piperazino group,4-methylpiperazino group, homopiperazino group, 2-oxopyrrolidino group,3-oxomorpholino group, and 2-oxomorpholino group.

Preferred examples of the ring C include those represented by thefollowing formulae:

Of these, particularly preferred are those represented by the followingformulae:

Of these, more preferred are those represented by the followingformulae:

R represents a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆alkylcarbonyl group, or a C₁ to C₆ alkylsulfonyl group.

Examples of the “C₁ to C₆ alkyl group” include methyl group, ethylgroup, propyl group, isopropyl group, isobutyl group, sec-butyl group,and tert-butyl group.

Examples of the “C₁ to C₆ alkylcarbonyl group” include acetyl group,propionyl group, and butyryl group.

Examples of the “C₁ to C₆ alkylsulfonyl group” include methylsulfonylgroup, ethylsulfonyl group, and propylsulfonyl group. Preferably, R is ahydrogen atom, methyl group, or acetyl group. Of these, hydrogen atom isparticularly preferred.

m

-   -   is 1 or 2, and preferably 1.        n    -   n is 2 or 3, and preferably 3.

Preferred examples of the compounds of the present invention include2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine,2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-5-oxopyrimido[4,5-b][1,5]diazocine,2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyridine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyrimidine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-2-(4-formylpiperazine-1-yl)-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(imidazole-1-yl)-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-(1,2,4-tetrazole-1-yl)pyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-2-[3-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,2-[3-(acetylamino)pyrrolidine-1-yl]-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(dimethylamino)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyrrolidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(piperidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(morpholine-4-yl)piperidine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(2-oxo-pyrrolidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine,2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepine,9-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido[4,5-b][1,5]diazocine,10-acetyl-2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-2-(1,1-dioxothiomorpholine-4-yl)-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,2-(4-acetylhomopiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(methylsulfonyl)piperazine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine,2-[4-(acetylamino)piperidine-1-yl]-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(methylsulfonylamino)piperidine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine.

Salts

Examples of pharmaceutically acceptable salts of the compounds of thepresent invention include those formed with inorganic acids, such ashydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, andthose formed with organic acids, such as acetic acid, maleic acid,fumaric acid, succinic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylicacid, stearic acid, and palmitic acid.

The compounds of the present invention or salts thereof may also existin the form of hydrates or solvates. The present invention encompassesany hydrates or solvates formed by the fused bicyclic pyrimidinederivatives of the general formula (1), including the preferredcompounds specifically mentioned above, or salts thereof. Examples ofthe solvents that can form solvates include methanol, ethanol,isopropanol, acetone, ethyl acetate, methylene chloride, anddiisopropylether.

Aside from racemic mixtures, the compounds of the present invention orsalts thereof may be provided in the form of optically active forms,stereoisomers, or atrop isomers.

Various synthetic techniques may be used to produce the compounds of thepresent invention. One commonly used production process of the compoundsof the present invention or salts thereof is described below.

(Step 1)

In this step, a carbonyl group is introduced into a compound (a)(wherein R⁹ is a leaving group that is eliminated later in Step 5 of theprocess, such as a halogen atom, a C₁ to C₆ alkylthio group, an arylthiogroup, a C₁ to C₆ alkylsulfonyl group, or an arylsulfonyl group, or R⁹is the ring C (the ring C is as described above)) to generate a compound(b) (wherein. R⁹ is as described above; R¹⁰ is a hydroxyl group, ahalogen atom, 1-imidazolyl group, 4-nitrophenoxy group, imidoyloxysuccinate group, a C₁ to C₆ alkoxyl group, or a benzyloxy group). Inthis process, the compound (b) is generated by first treating thecompound (a) with a base and then reacting the product with a compoundthat serves as a source of carbonyl group. The base for use in thisprocess may be a bulky base, such as lithium diisopropylamide. Theprocess is generally carried out-at a temperature of −100° C. to 20° C.and preferably at a temperature of −100° C. to −50° C. The compound thatserves as the source of carbonyl group for use in this process may be ahalide of a carboxylic acid, an imidazolide of a carboxylic acid, anactive ester of a carboxylic acid, an acid hydride, an orthoester, orcarbon dioxide. When R¹⁰ is a hydroxyl group, the compound (a) is firsttreated with the above-described base and carbon dioxide is used as thesource of carbonyl group. The process is terminated using a proper acid(e.g., hydrochloric acid).

(Step 2)

In this step, the compound (b) (wherein R⁹ and R¹⁰ are as describedabove) and the compound (c) (wherein R¹¹ is an alkoxycarbonyl group,such as t-butoxycarbonyl group and benzyloxycarbonyl group, and the ringB is as described above) are allowed to undergo condensation to generatea compound (d) (wherein R⁹, R¹¹, and the ring B are as described above).When R¹⁰ is a hydroxyl group, a suitable condensation agent for use inthe condensation reaction in this step may be dicyclohexylcarbodiimide(DCC), 3-ethyl-1-(3-dimethylaminopropyl)carbodimide hydrochloride(EDCI), or dimethylimidazolinium chloride (DMC). These condensationagents may be added in the form of a solid product or a solution in aproper solvent. A base may be used in the condensation reaction,including alkali carbonates, such as sodium hydrogen carbonate, orpotassium carbonate, and tertiary amines, such as triethylamine,diisopropylethylamine, N-methylmorpholine,diazabicyclo[5.4.0]-7-undecene, pyridine, 4-dimethylaminopyridine, or1,8-bis(dimethylamino)naphthalene. The solvent for use in thecondensation reaction may be any inert solvent that does not take partin the reaction, including N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane, ethyl ether,dimethoxyethane, ethylacetate, and dichloromethane. The condensationreaction may be carried out at −20° C. to 80° C. When the compound (b)for use in the condensation reaction in this step is any of a halide ofa carboxylic acid, an imidazolide of a carboxylic acid, or an activeester of a carboxylic acid, in which R¹⁰ is a halogen atom, a1-imidazolyl group, a 4-nitrophenoxy group or an imidoyloxy succinategroup, the reaction can be carried out by allowing the reactants toreact in the presence or absence of an organic base, such astriethylamine, diisopropylethylamine, pyridine or4-dimethylaminopyridine, or an inorganic base, such as sodium hydrogencarbonate or potassium carbonate, in a solvent, such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, ethyl ether, dimethoxyethane,ethylacetate, toluene or dichloromethane, at −20° C. to 80° C. for 30min. to 48 hours. When R¹⁰ is a C₁ to C₆ ester residue such as analkoxyl group and a benzyloxy group in the condensation reaction in thisstep, the reaction can be carried out by allowing the reactants to reactin the presence or absence of trimethylaluminum ortetraisopropoxytitanium or in the presence or absence of an acidic or abasic catalyst, such as p-toluenesulfonic acid, sodium methoxide,potassium t-butoxide, or sodium hydride, in a solvent, such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene,pyridine, quinoline, or dichloromethane, at 15° C. to 150° C. for 30min. to 48 hours.

(Step 3)

In this step, the compound (d) (wherein R⁹, R¹¹ and the ring B are asdescribed above) is stripped of R¹¹ and is cyclized to generate acompound (e) (wherein R⁹ and the ring B are as described above). Theremoval of R¹¹ can be carried out by treating the compound (d) with anacid, such as hydrogen chloride (which may be dissolved in a propersolvent, such as water, methanol, ethanol, ethyl acetate and1,4-dioxane) and trifluoroacetic acid, in a solvent, such as methanol,ethanol, ethyl acetate, and 1,4-dioxane, at 0 to 50° C. for 30 min. to24 hours. The subsequent cyclization may be carried out by allowing thereaction to take place in the presence or absence of an organic base,such as sodium-tert-butoxide or potassium-tert-butoxide, or an inorganicbase, such as sodium hydride, potassium carbonate, sodium carbonate,cesium carbonate or sodium acetate, in a solvent, such asN,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide,acetonitrile, tetrahydrofuran, dioxane, toluene, xylene, mesitylene,pyridine, quinoline, or dichloromethane, at 0° C. to 150° C. for 30 min.to 48 hours.

(Step 4)

In this step, the compound (e) (wherein R⁹ and the ring B are asdescribed above) and a compound (f) (wherein the ring A is as describedabove, Y is a halogen atom, OSO₂R¹² (wherein R¹² is a C₁ to C₆ alkylgroup, which may be substituted with halogen atoms), B(R¹³)₂ (whereinthe two R¹³ substituents are each independently a hydroxyl group, a C₁to C₆ alkyl group or a C₁ to C₆ alkoxyl group, or R¹³ substituents maybe bound to each other to form a ring), Li, MgBr, or ZnCl) are allowedto undergo either a cross-coupling reaction in the presence of atransitional metal catalyst, such as a palladium or nickel complex, or aGrignard reaction to generate a compound (g) (wherein R⁹ and the rings Aand B are as described above). Preferably, the process is carried out byusing an inert solvent that does not take part in the process. Examplesof the solvent include N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, acetonitrile, tetrahydrofuran, dioxane,dichloromethane, toluene, ethanol, or water. These solvents may be usedindividually or may be mixed with one another in any proportion.Examples of the palladium complexes for use in the process includepalladium chloride, palladium acetate, acetylacetonato palladium, andtetrakis(triphenylphosphine)palladium. Examples of the nickel complexesfor use in the process include bis(acetylacetonato)nickel,bis(1,5-cyclooctadiene)nickel, and tetrakis(triphenylphosphine)nickel.Each of these palladium or nickel complexes is used in an amount of0.001 to 1 equivalent, preferably in an amount of 0.01 to 0.1equivalents, with respect to the compound (e). When it is desired to usea ligand for the palladium or nickel complex in the process, the ligandmay be triphenylphosphine, tri-o-tolylphosphine, tri-2-furylphosphine,1,2-bis(diphenylphosphino)ethane, 1,1′-bis(diphenylphosphino)ferrocene,or 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl. Each of these ligands isused in an amount of 0.2 to 5 equivalents, preferably in an amount of0.3 to 3 equivalents, with respect to the palladium or nickel complex.Preferably, the process is carried out in the presence of a proper base.Among such bases are organic bases, including triethylamine,tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,lutidine, and collidine, and inorganic bases, including sodium hydrogencarbonate, sodium carbonate, potassium carbonate, calcium carbonate,cesium carbonate, and tripotassium phosphate. Each of these bases isused in an amount of 1 to 20 equivalents, preferably in an amount of 2to 10 equivalents, with respect to the compound (e). The cross-couplingreaction in this step is carried out by allowing the reactants toundergo the reaction at 15 to 150° C. preferably at 50 to 120° C. for 30min. to 24 hours.

(Step 5)

In this step, the compound (g) (wherein R⁹ and the rings A and B are asdescribed above) is reacted with a compound (h) to generate a compound(i) (wherein the rings A and B are as described above). (This step isomitted when R⁹ is the ring C.) The process can be carried out by usingthe compound (h) in an amount of 1 to 20 equivalents with respect to thecompound (g) and allowing the reaction to proceed in the presence orabsence of a base at 80 to 200° C. preferably at 100 to 150° C., for 30min. to 24 hours. A base may preferably be used, including organicbases, such as triethylamine, tributylamine, diisopropylethylamine,N-methylmorpholine, pyridine, lutidine, collidine, andN,N-dimethylaniline, and inorganic bases, such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, calcium carbonate,cesium carbonate, and tripotassium phosphate. When it is desired to usea solvent, such a solvent may be any inert solvent that does not takepart in the reaction, including N,N-dimethylformamide,N,N-dimethylacetamide, sulfolane, acetonitrile, tetrahydrofuran,dioxane, xylene, toluene, ethanol, or water.

The compounds (1) of the present invention can be isolated/purified byordinary means (for example, extraction, recrystallization,distillation, and chromatography). When the resulting compounds tend toform salts, such salts can be produced by ordinary techniques orequivalent techniques (for example, neutralization).

The compounds (1) of the present invention or salts thereof act astachykinin receptor antagonists and, in particular, as NK1 receptorantagonists and are thus useful as:

-   -   prophylactic or therapeutic agents for dysuria, including        defective bladder functions such as increased urinary frequency        and incontinence of urine;    -   prophylactic or therapeutic agents for disorders of digestive        tract such as ulcerative colitis and Crohn's disease;    -   prophylactic or therapeutic agents for vomiting induced by        exposure to X-ray, chemotherapy, pregnancy, migraine,        postoperative pains, decreased gastrointestinal motility, and        side effects of drugs;    -   prophylactic or therapeutic agents for vomiting induced by        exposure to X-ray, chemotherapy, pregnancy, migraine,        postoperative pains, decreased gastrointestinal motility, and        side effects of drugs; and    -   therapeutic agents for asthma, coughing, ache, migraine, tooth        pain, rheumatoid arthritis and other conditions.

The compounds (1) of the present invention or salts thereof may be usedindividually, or they may be formed into pharmaceutical compositionsalong with one or more pharmaceutically acceptable adjuvants.Specifically, the compounds of the present invention may be mixed withpharmaceutically acceptable carriers, excipients (such as starch,lactose, calcium phosphate, and calcium carbonate), lubricants (such asmagnesium stearate, calcium stearate talc, and stearic acid), binders(such as starch, cellulose crystals, carboxymethylcellulose, gum Arabic,polyvinylpyrrolidone, and alginic acid), disintegrating agents (such astalc, carboxymethylcellulose, and calcium), and diluents (such asphysiological saline, and aqueous solutions of glucose, mannitol, andlactose). Using ordinary techniques, the compounds of the presentinvention may be prepared as tablets, capsules, granules, powders, finegranules, ampules, or injections for oral or parenteral administration.While the dosage of the compounds (1) of the present invention or saltsthereof may vary depending on the type of salt, route of administration,and age and conditions of patients, a typical dose for humans and othermammals, for example, is in the range of 0.0001 to 300 mg/kg/day asmeasured by the amount of the compounds (1) of the present invention orsalts thereof. The compounds (1) or salts thereof may be administered ina single dose or several doses each day.

EXAMPLES

The present invention will now be described in detail with reference toExamples, Reference Examples, and Test Examples, as will an exemplaryproduction process of a starting material of the compounds (1) of thepresent invention, which is also a novel compound. It should beappreciated that the compounds of the present invention are not limitedto those described in the following examples and may be modified withoutdeparting from the scope and the spirit of the invention.

Reference Example 1

To a tetrahydrofuran solution of lithium diisopropylamide (which wasprepared by diluting diisopropylamine (3.0 ml) with tetrahydrofuran (25ml), followed by the addition of n-butyl lithium (13.6 ml, 1.52 mol/Lhexane solution) at −20° C. and stirring at −20° C. for 1 hour), atetrahydrofuran solution of 4,6-dichloro-2-(methylthio)pyrimidine (2.70g) (5 ml) was added at −78° C. and the mixture was stirred for 3 hours.Carbon dioxide gas was then bubbled through the reaction mixture for 10min. and water was added. The temperature of the mixture was thenallowed to rise to room temperature. Following the addition of 2 mol/Lhydrochloric acid (25 mL) to adjust pH to 1, the mixture was extractedwith ethyl acetate, and the extract was dried over anhydrous sodiumsulfate. The solvent was removed and the residue was washed with tolueneto obtain 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (1.93g, 58%).

MS(EI)m/z:238(M⁺)

HRMS(EI):. Calcd for C₆H₄Cl₂N₂O₂S: 237.9371; found: 237.9383

Reference Example 2

3-amino-1-(t-butoxycarbonylamino)propane (5.00 g) was dissolved inethanol (50 mL), followed by the addition of3,5-(bistrifluoromethyl)benzaldehyde (6.95 g) and stirring at 50° C. for1 hour. Following removal of the solvent under reduced pressure, theresulting residue was dissolved in methanol (50 mL). To this solution,sodium borohydride (2.18 g) was added and the mixture was stirred atroom temperature for 1 hour. Subsequently, the reaction mixture waschilled on an ice bath and water (5 ml) was added. The mixture was thenstirred for 1 hour and the solvent was removed. To the resultingresidue, water was added and the mixture was extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate. Thesolvent was then removed to give1-(t-butoxycarbonylamino)-3-[3,5-(trifluoromethyl)benzylamino]propane(11.5 g, 100%).

MS(FAB⁺)m/z: 401(M+H⁺)

HRMS(FAB⁺) Calcd for C₁₇H₂₃F₆N₂O₂: 401.1664; found: 401.1696

Reference Example 3

In a similar manner to Reference Example 1,3-amino-1-(t-butoxycarbonylamino)ethane (10.0 g) was reacted with3,5-(bistrifluoromethyl)benzaldehyde (15.1 g) to obtain1-(t-butoxycarbonyl)-3-[3,5-(trifluoromethyl)benzylamino]ethane (24.0 g,100%).

MS(FAB⁺)m/z: 387(M+H⁺)

HRMS(FAB⁺): Calcd for C₁₆H₂₁F₆N₂O₂: 387.1507; found: 387.1494

Reference Example 4

4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (Compound ofReference Example 1; 3.59 g) and N,N-dimethylformamide (0.2 mL) wereadded to thionyl chloride (11 mL). While heated, the mixture wasrefluxed for 2 hours. The reaction mixture was then distilled underreduced pressure to obtain a yellow residue.

Meanwhile,1-(t-butoxycarbonylamino)-3-[3,5-(trifluoromethyl)benzylamino]propane(Compound of Reference Example 2; 6.61 g) was dissolved intetrahydrofuran (40 mL) along with triethylamine (10 mL) While thissolution was chilled on an ice bath, a tetrahydrofuran solution of theyellow residue (10 ml) obtained above was added. The mixture was stirredfor 1 hour and then additional 3 hours at room temperature. The reactionmixture was then diluted with ethyl acetate, was sequentially washedwith water and a saturated aqueous solution of sodium chloride, and wasthen dried over anhydrous sodium sulfate. Following removal of thesolvent, the residue was purified on a silica gel column chromatography(ethyl acetate:hexane=1:3) to obtainN-[3,5-bis(trifluoromethyl)benzyl]-N-[3-(t-butoxycarbonylamino)propyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylicacid amide (8.49 g, 91%).

MS(FAB⁺)m/z: 621(M+H⁺)

HRMS(FAB⁺): Calcd for C₂₃H₂₅Cl₂F₆N₄O₃S: 621.0929; found: 621.0938

Reference Example 5

In a similar manner to Reference Example 4,4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid (Compound ofReference Example 1; 5.00 g) was reacted with1-(t-butoxycarbonylamino)-2-[3,5-(trifluoromethyl)benzylamino]ethane(Compound of Reference Example 3; 8.24 g) to obtainN-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(t-butoxycarbonylamino)ethyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylicacid amide (12.0 g, 94%).

MS(EI)m/z: 606(M⁺)

HRMS(EI): Calcd for C₂₂H₂₂Cl₂F₆N₄O₃S: 606.0694; found: 606.0716

Reference Example 6

3 mol/L hydrogen chloride-ethyl acetate (20 mL) was added toN-[3,5-bis(trifluoromethyl)benzyl]-N-[3-(t-butoxycarbonylamino)propyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylicacid amide (Compound of Reference Example 4; 8.23 g) while the solutionwas chilled on an ice bath. The reaction mixture was stirred for 1 hourand then another 1 hour at room temperature. Subsequently, the solventwas removed to obtainN-[3,5-bis(trifluoromethyl)benzyl]-N-(3-aminopropyl)-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylicacid amide hydrochloride (7.35 g, 100%).

MS(FAB⁺)m/z: 521 (M+H⁺)

HRMS(FAB⁺): Calcd for C₁₈H₁₇Cl₂F₆N₄OS: 521.0404; found: 521.0399

Reference Example 7

N-[3,5-bis(trifluoromethyl)benzyl]-N-(3-aminopropyl)-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylicacid amide hydrochloride (Compound of Reference Example 6; 3.35 g) wasdissolved in N,N-dimethylformamide (6 mL). To this solution, potassiumcarbonate (4.15 g) was added and the mixture was stirred at 100° C. for1 hour. The reaction mixture was diluted with ethyl acetate, wassequentially washed with water and a saturated aqueous solution ofsodium chloride, and was then dried over anhydrous sodium sulfate.Following removal of the solvent, the residue was purified on a silicagel column chromatography (ethyl acetate:hexane=1:1) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(2.05 g, 70%).

MS(EI)m/z: 484(M⁺)

HRMS(EI): Calcd for C₁₈H₁₅ClF₆N₄OS: 484.0559; found: 484.0598

Reference Example 8

3 mol/L hydrogen chloride-ethyl acetate (30 mL) was added toN-[3,5-bis(trifluoromethyl)benzyl]-N-[2-(t-butoxycarbonylamino)ethyl]-4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylicacid amide (Compound of Reference Example 5; 11.8 g) while the solutionwas chilled on an ice bath. The reaction mixture was stirred for 1 hourand then additional 1 hour at room temperature. The solvent was removedand the resulting residue was dissolved in N,N-dimethylformamide (20mL). To this solution, potassium carbonate (5.37 g) was added and themixture was stirred at 100° C. for 1 hour. The reaction mixture wasdiluted with ethyl acetate, was sequentially washed with water and asaturated aqueous solution of sodium chloride, and was then dried overanhydrous sodium sulfate. Following removal of the solvent, the residuewas purified on a silica gel column chromatography (ethylacetate:hexane=2:1) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin(6.22 g, 68%).

MS(EI)m/z: 470(M⁺)

HRMS(EI): Calcd for C₁₇H₁₃ClF₆N₄OS: 470.0403; found: 470.0385

Reference Example 9

6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compoundof Reference Example 7; 1.50 g) was dissolved in N,N-dimethylformamide(6 mL). To this solution, sodium hydride (185 mg, 60% oil suspension)was added and the mixture was stirred at room temperature for 1 hour.Methyl iodide (0.4 mL) was then added and the mixture was furtherstirred at room temperature for 1 hour. The reaction mixture was dilutedwith ethyl acetate, was sequentially washed with water and a saturatedaqueous solution of sodium chloride, and was then dried over anhydroussodium sulfate. Following removal of the solvent, the residue waspurified on a silica gel column-chromatography (ethylacetate:hexane=1:1) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-10-methyl-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(1.36 g, 88%).

MS(EI)m/z: 498(M⁺)

HRMS(EI): Calcd for C₁₉H17ClF₆N₄OS: 498.0716; found: 498.0746

Reference Example 10

Phenylboric acid (732 mg), tetrakis(triphenylphosphine)palladium (289mg), toluene (15 ml), 1,4-dioxane (8 ml) and a 2 mol/L aqueous solutionof sodium carbonate (15 ml) were added to6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 7; 2.43 g). While heated, the mixture wasrefluxed for 5 hours under a stream of argon gas. Subsequently, thereaction mixture was diluted with ethyl acetate, was washed with a 2mol/L aqueous solution of sodium carbonate, and was then dried overanhydrous sodium sulfate. The solvent was removed and the resultingresidue was purified on a silica gel column chromatography (ethylacetate:hexane=1:1) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine(2.63 g, 100%).

MS(EI)m/z: 526(M⁺)

HRMS(EI): Calcd for C₂₄H₂₀F₆N₄OS: 526.1262; found: 526.1262

Reference Example 11

In a similar manner to Reference Example 10,6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 7; 2.43 g) was reacted with4-fluorophenylboric acid (840 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(2.49 g, 91%).

MS(EI)m/z: 544(M⁺)

HRMS(EI): Calcd for C₂₄H₁₉F₇N₄OS: 544.1168; found: 544.1165

Reference Example 12

In a similar manner to Reference Example 10,6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 7; 2.43 g) was reacted with2-methoxyphenylboric acid (912 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(2.47 g, 89%).

MS(EI)m/z: 556(M⁺)

HRMS(EI): Calcd for C₂₅H₂₂F₆N₄O₂S: 556.1368; found: 556.1339

Reference Example 13

In a similar manner to Reference Example 10,6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 7; 485 mg) was reacted with2-methylphenylboric acid (163 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(540 mg, 100%).

MS(EI)m/z: 540(M⁺)

HRMS(EI):Calcd for C₂₅H₂₂F₆N₄OS: 540.1419; found: 540.1390

Reference Example 14

In a similar manner to Reference Example 10,6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin(Compound of Reference Example 8; 2.36 g) was reacted with2-methylphenylboric acid (816 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin(2.63 g, 100%).

MS(EI)m/z: 526(M⁺)

HRMS(EI): Calcd for C₂₄H₂₀F₆N₄OS: 526.1262; found: 526.1232

Reference Example 15

In a similar manner to Reference Example 10,6-[3,5-bis(trifluoromethyl)benzyl]-4-chloro-5,6,7,8,9,10-hexahydro-10-methyl-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compoundof Reference Example 9; 1.25 g) was reacted with 2-methylphenylboricacid (410 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(1.39 g, 100%).

MS(EI)m/z: 554(M⁺)

HRMS(EI): Calcd for C₂₆H₂₄F₆N₄OS: 554.1575; found: 554.1599

Reference Example 16

6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 10; 2.46 g) was dissolved intetrahydrofuran (15 mL). While the solution was chilled on an ice bath,3-chlorobenzoic acid (2.42 g) was added and the mixture was stirred atroom temperature for 3 hours. Subsequently, the reaction mixture waspurified on a silica gel chromatography (ethyl acetate:hexane=2:1) toobtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine(1.84 g, 71%).

MS(EI)m/z: 558(M⁺)

HRMS(EI): Calcd for C₂₄H₂₀F₆N₄O₃S: 558.1160; found: 558.1193

Reference Example 17

In a similar manner to Reference Example 16,6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 11; 2.21 g) was used to obtain6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(2.10 g, 90%).

MS(EI)m/z: 576(M⁺)

HRMS(EI): Calcd for C₂₄H₁₉F₇N₄O₃S: 576.1066; found: 576.1104

Reference Example 18

In a similar manner to Reference Example 16,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 12; 2.24 g) was used to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(2.09 g, 88%).

MS(EI)m/z: 588(M⁺)

HRMS(EI): Calcd for C₂₅H₂₂F₆N₄O₄S: 588.1266; found: 588.1238

Reference Example 19

In a similar manner to Reference Example 16,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 13; 490 mg) was used to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(335 mg, 65%).

MS(EI)m/z: 572(M⁺)

HRMS(EI): Calcd for C₂₅H₂₂F₆N₄O₃S: 572.1317; found: 572.1290

Reference Example 20

In a similar manner to Reference Example 16,6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-2-(methylthio)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin(Compound of Reference Example 14; 2.50 g) was used to obtain6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin(410 mg, 15%).

MS(EI)m/z: 558(M⁺)

HRMS(EI): Calcd for C₂₄H₂₀F₆N₄O₃S: 558.1160; found: 558.1156

Reference Example 21

In a similar manner to Reference Example 16,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylthio)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 15; 1.37 g) was used to obtain6-(3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(1.24 g, 86%).

MS(EI)m/z: 586(M⁺)

HRMS(EI): Calcd for C₂₆H₂₄F₆N₄O₃S: 586.1473; found: 586.1436

Example 1

1-acetylpiperazine(23.1 mg), diisopropylethylamine(0.1 mL), and1,4-dioxane (1 mL) were added to6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 16; 83.8 mg). While heated, the mixturewas refluxed for 5 hours. Subsequently, the reaction mixture was dilutedwith ethyl acetate, was sequentially washed with water and a saturatedaqueous solution of sodium chloride, and was then dried over anhydroussodium sulfate. Following removal of the solvent, the residue waspurified on a silica gel column chromatography (ethylacetate:methanol=10:1) to obtain2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-5-oxo-4-phenylpyrimido[4,5-b][1,5]diazocine(63.0 mg, 69%).

MS(EI)m/z: 606(M⁺)

HRMS(EI): Calcd for C₂₉H₂₈F₆N₆O₂: 606.2178: found: 606.2158

Example 2

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 17; 86.5 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydro-5-oxopyrimido[4,5-b][1,5]diazocine(76.4 mg, 82%).

MS(EI)m/z: 624(M⁺)

HRMS(EI): Calcd for C₂₉H₂₇F₇N₆O₂: 624.2084; found: 624.2070

Example 3

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 18; 88.3 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(77.3 mg, 81%).

MS(EI)m/z: 636(M⁺)

HRMS(EI): Calcd for C₃₀H₃₀F₆N₆O₃: 636.2284; found: 636.2323

Example 4

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19 ;85.9 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(70.0 mg, 75%).

MS(EI)m/z: 620(M⁺)

HRMS(EI): Calcd for C₃₀H₃₀F₆N₆O₂: 620.2334; found: 620.2319

Example 5

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with morpholine(15.7 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido[4,5-b][1,5]diazocine(87.8 mg, 100%).

MS(EI)m/z: 579(M⁺)

HRMS(EI): Calcd for C₂₈H₂₇F₆N₅O₂: 579.2069; found: 579.2051

Example 6

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with1-(pyridine-2-yl)piperazine (29.4 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyridine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine(95.7 mg, 97%).

MS(EI)m/z: 655(M⁺)

HRMS(EI): Calcd for C₃₃H₃₁F₆N₇O: 655.2494; found: 655.2512

Example 7

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with1-(pyrimidine-2-yl)piperazine (30.0 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyrimidine-2-yl)piperazine-1-yl]pyrimido[4,5-b][1,5]diazocine(48.1 mg, 49%).

MS(EI)m/z: 656(M⁺)

HRMS(EI): Calcd for C₃₂H₃₀F₆N₈O: 656.2447; found: 656.2435

Example 8

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with1-formylpiperazine(20.6 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-2-(4-formylpiperazine-1-yl)-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(5.6 mg, 6%).

MS(EI)m/z: 606(M⁺)

HRMS(EI): Calcd for C₂₉H₂₈F₆N₆O₂: 606.2178; found: 606.2214

Example 9

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with sodium saltof imidazole (16.2 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(imidazole-1-yl)-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(61.0 mg, 73%).

MS(EI)m/z: 560(M⁺)

HRMS(EI): Calcd for C₂₇H₂₂F₆N₆O: 560.1759; found: 560.1727

Example 10

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with sodium saltof 1,2,4-tetrazole (16.4 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-(1,2,4-tetrazole-1-yl)pyrimido[4,5-b][1,5]diazocine(81.1 mg, 96%).

MS(EI)m/z: 561(M⁺)

HRMS(EI): Calcd for C₂₆H₂₁F₆N₇O: 561.1712; found: 561.1702

Example 11

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with3-(ethoxycarbonyl)piperidine (28.3 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-2-[3-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(76.0 mg, 78%).

MS(EI)m/z: 649(M⁺)

HRMS(EI): Calcd for C₃₂H₃₃F₆N₅O₃: 649.2488; found: 649.2511

Example 12

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with4-(ethoxycarbonyl)piperidine (28.3 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(ethoxycarbonyl)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(97.0 mg, 100%).

MS(EI)m/z: 649(M⁺)

HRMS(EI): Calcd for C₃₂H₃₃F₆N₅O₃: 649.2488; found: 649.2465

Example 13

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with3-(acetylamino)pyrrolidine (23.1 mg) to obtain2-[3-(acetylamino)pyrrolidine-1-yl]-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(92.6 mg, 99%).

MS(EI)m/z: 620(M⁺)

HRMS(EI) : Calcd for C₃₀H₃₀F₆N₆O₂: 620.2334; found: 620.2325

Example 14

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Example 19; 85.9 mg) was reacted with4-(dimethylamino)piperidine (23.1 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-2-[4-(dimethylamino)piperidine-1-yl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(80.5 mg, 86%).

MS(EI)m/z: 620(M⁺)

HRMS(EI): Calcd for C₃₁H₃₄F₆N₆O: 620.2698; found: 620.2662

Example 15

In a similar-manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with4-(pyrrolidine-1-yl)piperidine (27.8 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(pyrrolidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine(89.5 mg, 92%).

MS(EI)m/z: 646(M⁺)

HRMS(EI): Calcd for C₃₃H₃₆F₆N₆O: 646.2855; found: 646.2825

Example 16

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with4-(piperidine-1-yl)piperidine (30.3 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(piperidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine(85.3 mg, 86%).

MS(EI)m/z: 660(M⁺)

HRMS(EI): Calcd for C₃₄H₃₈F₆N₆O: 660.3011; found: 660.3026

Example 17

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with4-(morpholine-4-yl)piperidine (30.7 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(morpholine-4-yl)piperidine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine(86.5 mg, 87%).

MS(EI)m/z: 662(M⁺)

HRMS(EI): Calcd for C₃₃H₃₆F₆N₆O₂: 662.2804; found: 662.2798

Example 18

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg) was reacted with4-(2-oxopyrrolidine-1-yl)piperidine (30.3 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxo-2-[4-(2-oxopyrrolidine-1-yl)piperidine-1-yl]pyrimido[4,5-b][1,5]diazocine(96.0 mg, 97%).

MS(EI)m/z: 660(M⁺)

HRMS(EI): Calcd for C₃₃H₃₄F₆N₆O₂: 660.2647; found: 660.2648

Example 19

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-2-(methylsulfonyl)-4-(2-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin(Compound of Reference Example 20; 83.8 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-4-(2-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin(43.8 mg, 46%).

MS(EI)m/z: 606(M⁺)

HRMS(EI): Calcd for C₂₉H₂₈F₆N₆O₂: 606.2178; found: 606.2166

Example 20

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 21; 88.0 mg) was reacted with1-acetylpiperazine (23.1 mg) to obtain9-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(78.6 mg, 83%).

MS(EI)m/z: 634(M⁺)

Example 21

In a similar manner to Example 1,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 21; 88.0 mg) was reacted with morpholine(15.7 mg) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-10-methyl-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido(4,5-b][1,5]diazocine(81.8 mg, 92%).

MS(EI)m/z: 593(M⁺)

HRMS(EI): Calcd for C₂₉H₂₉F₆N₅O₂: 593.2225; found: 593.2189

Example 22

1-acetylpiperazine (23.1 mg), diisopropylethylamine (0.1 mL), and1,4-dioxane (1 mL) were added to6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg). While heated, the mixturewas refluxed for 5 hours. The solvent was removed and anhydrous aceticacid (0.5 mL) and pyridine (0.1 mL) were added, followed by stirring at100° C. for 3 hours. Subsequently, the reaction mixture was diluted withethyl acetate, was sequentially washed with water and a saturatedaqueous solution of sodium chloride, and was then dried over anhydroussodium sulfate. Following removal of the solvent, the residue waspurified on a silica gel column chromatography (ethylacetate:methanol=10:1) to obtain10-acetyl-2-(4-acetylpiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(90.2 mg, 91%).

MS(EI)m/z: 662(M⁺)

HRMS(EI): Calcd for C₃₂H₃₂F₆N₆O₃: 662.2440; found: 662.2435

Example 23

Thiomorpholine (18.6 mg), diisopropylethylamine (0.1 mL) and 1,4-dioxane(1 L) were added to6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg). While heated, the mixturewas refluxed for 5 hours. Subsequently, the reaction mixture was dilutedwith ethyl acetate, was washed with water, and was then dried overanhydrous sodium sulfate. Following removal of the solvent,tetrahydrofuran (1 mL) and 3-chlorobenzoic acid (77.7 mg) were added andthe mixture was further stirred at room temperature for 3 hours.Subsequently, the reaction mixture was diluted with ethyl acetate, waswashed with water, and was then dried over anhydrous sodium sulfate.Following removal of the solvent, the residue was purified on a silicagel column chromatography (ethyl acetate) to obtain6-[3,5-bis(trifluoromethyl)benzyl]-2-(1,1-dioxothiomorpholine-4-yl)-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(55.4 mg, 59%).

MS(EI)m/z: 627(M⁺)

HRMS(EI): Calcd for C₂₈H₂₇F₆N₅O₃S: 627.1739; found: 627.1745

Example 24

1-(t-butoxycarbonyl)homopiperazine (36.1 mg), diisopropylethylamine (0.1mL) and 1,4-dioxane (1 mL) were added to6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg). While heated, the mixturewas refluxed for 5 hours. The reaction mixture was then diluted withethyl acetate, was washed with water, and was then dried over anhydroussodium sulfate. The solvent was removed and 3 mol/L hydrogenchloride/ethyl acetate (1 mL) was added while the residue was chilled onan ice bath. The mixture was stirred for 30 min and then additional 1hour at room temperature. Following removal of the solvent, the residuewas dissolved in tetrahydrofuran (1 mL). While the residue was chilledon an ice bath, triethylamine (0.1 mL) and anhydrous acetic acid (0.05mL) were added and the mixture was stirred at room temperature for 30min. Subsequently, the reaction mixture was diluted with ethyl acetate,was washed with water, and was then dried over anhydrous sodium sulfate.Following removal of the solvent, the residue was purified on a silicagel column chromatography (ethyl acetate:methanol=10:1) to obtain2-(4-acetylhomopiperazine-1-yl)-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(70.7 mg, 74%).

MS(EI)m/z: 634(M⁺)

HRMS(EI): Calcd for C₃₁H₃₂F₆N₆O₂: 634.2491; found: 634.2483

Example 25

In a similar manner to Example 24,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg),1-(t-butoxycarbonyl)piperazine (33.5 mg) and methylsulfonylchloride(0.04 mL) were reacted to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(methylsulfonyl)piperazine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine(74.1 mg, 75%).

MS(EI)m/z: 656(M⁺)

HRMS(EI): Calcd for C₂₉H₃₀F₆N₆O₃S: 656.2004; found: 656.1992

Example 26

In a similar manner to Example 24,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg),4-(t-butoxycarbonylamino)piperidine (36.1 mg) and acetic anhydride (0.05mL) were reacted to obtain2-[4-(acetylamino)piperidine-1-yl]-6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(71.2mg, 75%).

MS(EI)m/z: 634(M⁺)

HRMS(EI): Calcd for C₃₁H₃₂F₆N₆O₂: 634.2491; found: 634.2483

Example 27

In a similar manner to Example 24,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 19; 85.9 mg),4-(t-butoxycarbonylamino)piperidine (36.1 mg) andmethanesulfonylchloride (0.04 mL) were reacted to obtain6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(methylsulfonylamino)piperidine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine(45.2 mg, 45%).

MS(EI)m/z: 670(M⁺)

HRMS(EI): Calcd for C₃₀H₃₂F₆N₆O₃S: 670.2161; found: 670.2151

Example 28

In a similar manner to Example 23,6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-2-(methylsulfonyl)-4-(2-methoxyphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(Compound of Reference Example 12; 118 mg) and thiomorpholine(100 mg)were reacted to obtain6-[3,5-bis(trifluoromethyl)benzyl]-2-(1,1-dioxothiomorpholine-4-yl)-5,6,7,8,9,10-hexahydro-4-(2-methoxyphenyl)-5-oxopyrimido[4,5-b][1,5]diazocine(76.9 mg, 59%).

MS(EI)m/z: 643(M⁺)

HRMS(EI): Calcd for C₂₈H₂₇F₆N₅O₄S: 643.1688; found: 643.1702

Evidence of the effectiveness of the compounds of the present inventionis provided below with reference to Test Examples.

Test Examples

(1) Test for NK1 Receptor Antagonist

The method used was according to the method proposed by S. Dion etal.(Dion et al., Life Sciences 41(1987): 2269), to which minormodifications were made.

Guinea pigs were stunned by a blow on the head and were exsanguinatedfrom the carotid artery and ilea were isolated. The ileum was mounted inan organ bath containing Tyrode's solution which was maintained at 32°C. and gased with 95% O₂ and 5% CO₂. The ileum was subjected to aresting tension of 1-gram and allowed to equilibrate for 20 minutesbefore the experiment was started. As a control, aconcentration-response curve for substance P in the absence of any oftest compounds was used. The NK1 receptor antagonist activity of eachtest compound was determined by a concentration-response curve obtainedby pretreating at least three concentrations of the test compound for 10minutes and subsequently applying substance P in a cumulative manner.The Kb values were determined according to the method of Schild and theresults are shown in Table 1 (Schild Brit. J. Pharmacol. 14(1959): 48).

The composition of the Tyrode's solution was as follows: NaCl=136.9,KCl=2.7, CaCl₂.2H₂O=2.5, MgCl₂.6H₂O=1.0, NaH₂PO₄.2H2O=0.4, NaHCO₃=11.9,glucose=11.1(mmol/L) TABLE 1 Test Compounds Kb(nmol/L) Compound ofExample 4 0.148 Compound of Example 20 0.324 Compound of Example 210.420 Compound of Example 22 0.0794 Compound of Example 28 0.169TAK-637* 0.269*Compound described in Example 18 in Japanese Patent Laid-OpenPublication No. Hei 9-263585

As can be seen from the results of Table 1, the compounds (1) or saltsthereof have proven to be effective NK1 receptor antagonists.

(2) Cystometry Test on Guinea Pigs

The method used was according to the method proposed by J S. Peterson etal. (Peterson J S. et al., J. Pharmacol. Methods 21(1989): 231), towhich minor modifications were made.

Guinea pigs were anesthetized with halothane and the tenth thoracicspinal cord was cut in each animal. Subsequently, both ureters wereligated and were cut on the kidney-side. Polyethylene catheters wereinserted into the bladder to provide an injection pathway forphysiological saline and a pathway for the measurement of intravesicalpressure. Each animal was restricted in a Ballman cage and was left formore than 2 hours. Subsequently, room-temperature saline was injectedthrough the bladder catheter into the bladder at a rate of 6 mL/hr toconduct a cystometry test. Once the effective bladder capacity wasstabilized, a test compound was intravenously administered into thejugular vein. The effective bladder capacity is defined as the volume ofsaline injected from one urination to the next. The effect of each testcompound was determined as the increase in the average bladder volume,which was determined based on the average bladder volume measured 30minutes prior to the administration of the test compound and the averagebladder volume measured every 30 minutes after the administration of thetest compound. The results are shown in Table 2. TABLE 2 Dose Increasein (i.v.) bladder Test compounds mg/kg capacity (%) Compound of Example4 0.3 43.0 TAK-637* 0.3 12.0 1 23.8 3 20.5*Compound described in Example 18 in Japanese Patent Laid-OpenPublication No. Hei 9-263585

As can be inferred from the results of Table 2, the compounds (1) orsalts thereof have a better ability to increase the effective bladdercapacity than TAK-637 in terms of the potency as well as the maximumeffects.

Industrial Applicability

As set forth, the present invention has been devised based on thediscovery that the novel fused bicyclic pyrimidine derivatives and saltsthereof act as effective tachykinin receptor antagonists.

In particular, not only have the compounds of the present invention haveproven to act as NK1 receptor antagonists, but they have also beenshown, by the Test Examples above, to have better effects than theconventional compounds.

Specifically, the compounds of the present invention proved to exhibitsignificantly higher pharmacological effects as compared to TAK-637, aknown compound, when tested for their effects on dysuria, atachykinin-mediated disorder, by cystometry, during which the ability ofeach of the compounds to increase the effective bladder capacity wasdetermined in guinea pigs with broken spinal cords. In brief, thecompounds of the present invention exhibited pharmacological effectscomparable to the conventional TAK-637 compound at smaller doses. Whencompared at the same doses, the compounds of the present inventionbrought about significantly better pharmacological effects and elicitedhigher maximum effects than TAK-637.

In addition, the compounds of the present invention and salts thereofexhibit little toxicity and are thus proven to be highly safe.Accordingly, the compounds of the present invention and salts thereof,which are effective tachykinin antagonists, are of significantusefulness in the treatment of various pathological conditions includingpollakiuria.

1. A fused bicyclic pyrimidine derivative represented by the followinggeneral formula (1), or a salt thereof:

wherein the rings A and B are each a benzene ring, which may have 1 to 3substituents (any adjacent two of which may be bound to one another toform a ring) that are each independently selected from the groupconsisting of a halogen atom, a C₁ to C₆ alkyl group, which may besubstituted with a halogen atom, and a C₁ to C₆ alkoxyl group; the ringC is a 5- to 7-membered nitrogen-containing ring, which may contain,aside from the nitrogen atom, 1 to 3 heteroatoms selected from the groupconsisting of a nitrogen atom, a sulfur atom, and an oxygen atom; thering C may further contain a substituent (a substituent selected fromthe group consisting of a C₁ to C₆ alkyl group, a hydroxyl group, a C₁to C₆ alkoxyl group, a formyl group, a C₁ to C₆ alkylcarbonyl group, aC₁ to C₆ alkoxycarbonyl group, a carbamoyl group, a mono- ordi-substituted C₁ to C₆ alkylcarbamoyl group, a C₁ to C₆ alkylsulfonylgroup, an amino group, a mono- or di-substituted C₁ to C₆ alkylaminogroup, a C₁ to C₆ alkylcarbonylamino group, a C₁ to C₆alkoxycarbonylamino group, a C₁ to C₆ alkylsulfonylamino group, an oxogroup, a 6-membered aromatic heterocyclic group, and a substituentrepresented by the following formula:

wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ring,which may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms); R is a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆alkylcarbonyl group, or a C₁ to C₆ alkylsulfonyl group; m is 1 or 2; andn is 2 or
 3. 2. The fused bicyclic pyrimidine derivative according toclaim 1 represented by the following general formula (1a), or a saltthereof:

wherein the ring A is a benzene ring, which may have 1 to 3 substituents(any adjacent two of which may be bound to one another to form a ring)that are each independently selected from the group consisting of ahalogen atom, a C₁ to C₆ alkyl group, which may be substituted with ahalogen atom, and a C₁ to C₆ alkoxyl group; the ring C is a 5- to7-membered nitrogen-containing ring, which may contain, aside from thenitrogen atom, 1 to 3 heteroatoms selected from the group consisting ofa nitrogen atom, a sulfur atom, and an oxygen atom; the ring C mayfurther contain a substituent (a substituent selected from the groupconsisting of a C₁ to C₆ alkyl group, a hydroxyl group, a C₁ to C₆alkoxyl group, a formyl group, a C₁ to C₆ alkylcarbonyl group, a C₁ toC₆ alkoxycarbonyl group, a carbamoyl group, a mono- or di-substituted C₁to C₆ alkylcarbamoyl group, a C₁ to C₆ alkylsulfonyl group, an aminogroup, a mono- or di-substituted C₁ to C₆ alkylamino group, a C₁ to C₆alkylcarbonylamino group, a C₁ to C₆ alkoxycarbonylamino group, a C₁ toC₆ alkylsulfonylamino group, an oxo group, a 6-membered aromaticheterocyclic group, and a substituent represented by the followingformula:

wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ring,which may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms); R is a hydrogen atom, a C₁ to C₆ alkyl group, a C₁ to C₆alkylcarbonyl group, or a C₁ to C₆ alkylsulfonyl group; and n is 2 or 3.3. The fused bicyclic pyrimidine derivative according to claim 2, or asalt thereof, wherein in the general formula (1a), the ring C isrepresented by the following formula:

wherein R¹ is a hydroxyl group, a C₁ to C₆ alkoxy group, a formyl group,a C₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group, acarbamoyl group, a mono- or di-substituted C₁ to C₆ alkylcarbamoylgroup, an amino group, a mono- or di-substituted C₁ to C₆ alkylaminogroup, a C₁ to C₆ alkylcarbonylamino group, a C₁ to C₆alkoxycarbonylamino group, a C₁ to C₆ alkylsulfonylamino group, an oxogroup, a 6-membered aromatic heterocyclic group, or a substituentrepresented by the following formula:

wherein the ring D is a 3- to 7-membered nonaromatic heterocyclic ring,which may contain, aside from the nitrogen atom, 1 to 3 heteroatomsselected from the group consisting of a nitrogen atom, a sulfur atom,and an oxygen atom and may further contain 1 or 2 oxo-substituted carbonatoms.
 4. The fused bicyclic pyrimidine derivative according to claim 2,or a salt thereof, wherein in the general formula (1a), the ring C isrepresented by the following formula:

wherein X is —O— or —S(O)_(q)—; and q is 0, 1, or
 2. 5. The fusedbicyclic pyrimidine derivative according to claim 2, or a salt thereof,wherein in the general formula (1a), the ring C is a group representedby the following formula:

wherein R² is a hydrogen atom, a C₁ to C₆ alkyl group, a formyl group, aC₁ to C₆ alkylcarbonyl group, a C₁ to C₆ alkoxycarbonyl group, acarbamoyl group, a mono- or di-substituted C₁ to C₆ alkylcarbamoyl groupor a C₁ to C₆ alkylsulfonyl group; and r is 1 or
 2. 6. The fusedbicyclic pyrimidine derivative according to claim 2, or a salt thereof,wherein in the general formula (1a), the ring C is represented by thefollowing formula:

wherein R² is an acetyl group or a methylsulfonyl group; and r is 1 or2.
 7. The fused bicyclic pyrimidine derivative according to claim 2, ora salt thereof, wherein in the general formula (1a), the ring C isrepresented by the following formula:


8. The fused bicyclic pyrimidine derivative according to claim 7, or asalt thereof, wherein in the general formula (1a), n is
 3. 9. The fusedbicyclic pyrimidine derivative according to claim 7, or a salt thereof,wherein in the general formula (1a), R is a hydrogen atom, and n is 3.10. A method for introducing a tachykinin receptor antagonist in apatient, which comprises administering to the patient a therapeuticallyeffective amount of a fused bicyclic pyrimidine derivative according toclaim 1, or a salt thereof.
 11. A method of introducing an NK1 receptorantagonist in a patient, which comprises administering to the patient atherapeutically effective amount of a fused bicyclic pyrimidinederivative according to claim 1, or a salt thereof.
 12. A method ofpreventing or treating dysuria, including defective bladder functionssuch as increased urinary frequency and incontinence of urine, in apatient, which comprises administering to the patient a therapeuticallyeffective amount of a fused bicyclic pyrimidine derivative according toclaim 1, or a salt thereof.
 13. A method of preventing or treatingdisorders of digestive tract such as ulcerative colitis and Crohn'sdisease, a patient, which comprises administering to the patient atherapeutically effective amount of a fused bicyclic pyrimidinederivative according to claim 1, or a salt thereof.
 14. A method ofpreventing or treating vomiting induced by exposure to X-ray,chemotherapy, pregnancy, migraine, postoperative pains, decreasedgastrointestinal motility, and side effects of drugs, in a patient,which comprises administering to the patient a therapeutically effectiveamount of a fused bicyclic pyrimidine derivative according to claim 1,or a salt thereof.
 15. A method of treating conditions, such as asthma,coughing, ache, migraine, tooth pain, and rheumatoid arthritis, in apatient, which comprises administering to the patient a therapeuticallyeffective amount of a fused bicyclic pyrimidine derivative according toclaim 1, or a salt thereof.
 16. A composition comprising a fusedbicyclic pyrimidine derivative according to claim 1, or a salt thereof,and a pharmaceutically acceptable adjuvant.